Administration of methamphetamine (METH) to rats and nonhuman primates causes loss of terminals in the nigrostriatal dopaminergic system. The mechanism by which METH causes its neurotoxicity is not known. To evaluate further the role of oxyradicals in METH‐induced neurotoxicity, we have tested its effects in CuZn superoxide dismutase (SOD) transgenic (Tg) mice, which express the human CuZnSOD gene. In non‐Tg mice, acute METH administration causes significant decreases in levels of dopamine (DA) and 3, 4‐dihydroxyphenylacetic acid (DOPAC) in the striata and cortices of non‐Tg mice. In contrast, there were no significant decreases in cortical or striatal DA in the SOD‐Tg mice. The effects of METH on DOPAC were also attenuated in both structures of these SOD‐Tg mice. Chronic METH administration caused decreases in levels of striatal DA and DOPAC in the non‐ Tg mice, whereas the SOD‐Tg mice were not affected. These results suggest that METH‐induced dopaminergic toxicity in mice may be secondary to increased production of reactive oxygen species such as the superoxide radical.
METH is a monoaminergic toxic that destroys dopamine terminals in vivo. Oxidative mechanisms associated with DA metabolism are thought to play an important role in its toxic effects. These ideas were supported by the demonstration that CuZn-superoxide dismutase (CuZnSOD) transgenic mice were protected against the toxic effects of the drug. In the present study, we sought to determine if nitric oxide (NO) production was also involved in METH-induced neurotoxicity using primary cultures obtained from fetal rat mesencephalon. METH caused dose- and time-dependent cell death in vitro. Blockade of nitric oxide (NO) formation with several nitric oxide (NO) synthase blockers attenuated METH-mediated toxicity. Moreover, inhibition of ADP-ribosylation with nicotinamide and benzamide also provided protection against the toxicity of the drug. These results, together with our previous results in transgenic mice, support a role for free radicals in METH-induced toxic effects.
1. Inhibitors of nitric oxide (NO) formation or ADP-ribosylation attenuate methamphetamine (METH)- and methylenedioxymetamphetamine (MDMA)-induced neurotoxicity on dopaminergic and serotonergic cells in primary cultures. 2. They also prevent METH-induced reactive gliosis in dopaminergic cultures. 3. Overexpression of superoxide dismutase (SOD) in cells obtained from SOD-transgenic mice also attenuates drug-induced toxicity. 4. These data indicate a role for oxygen-based and NO free radicals in the mechanisms of cell death associated with drugs of abuse in vitro.
Methamphetamine (METH) caused dose-dependent increases in AP-1 DNA-binding activity in both nontransgenic (Non-Tg) and CuZn-SOD transgenic (SOD-Tg) mice. However, the increases in SOD-Tg mice were less prominent than those observed in Non-Tg animals. The time-course of METH-induced AP-1 changes was similar in both strains of mice. AP-1 binding activity showed an initial increase at 1 h, peaked at 3 h, and then gradually declined. AP-1 binding activity was back to normal by the 72-h time point. Regional analyses of METH effects revealed increases in the caudate putamen and cerebellum, with the striatum showing relatively higher METH-induced AP-1 DNA-binding activation. These regional effects were also attenuated in the SOD-Tg mice. These data indicate that METH-induced stimulation of AP-1 DNA-binding depends on cellular redox status. These results are consistent with in vitro studies that have reported that several transcription factors are regulated through redox mechanisms.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.